DO SINGLE-NUCLEOTIDE POLYMORPHISMS IN THE AIP AND MEN1 GENES PREDISPOSE INDIVIDUALS TO THE DEVELOPMENT OF FAMILIAL ISOLATED PITUITARY TUMORS?

Abstract

Pituitary tumors are quite common and can occur in a familial setting such as MEN-1 and Carney complex (CNC). Recently, germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene have been found in 16% of all patients who were diagnosed with pituitary adenomas (PAs) secreting growth hormone. We here report an AA family with non-MEN-1/CNC familial isolated PA in an attempt to identify predisposed individuals. Clinical characterization of such families may lead to the discovery of new genetic syndromes. A 55-year-old AA man was admitted to the UMMC with new-onset left-sided weakness. He reported a 6-month history of recurrent headaches and diplopia but no seizures. The patient denied any history of renal calculi or MEN-1/CNC associated features in himself and his family members. MRI of the pituitary showed a 5.5 × 3.6 × 4 cm sellar mass with suprasellar extension. Biochemical testing revealed secondary adrenal insufficiency, hypothyroidism, hypogonadism, and GH deficiency. Prolactin and alpha subunit were normal. After glucocorticoid and thyroid hormones had been replaced, he underwent transsphenoidal resection of the adenoma. Final pathology revealed a null cell tumor with immunohistochemical results that were negative for anterior pituitary hormones. FH revealed that he had a brother with a pituitary tumor who presented similarly at the age of 50 with the final diagnosis of a null cell tumor with immunohistochemical results negative for prolactin and growth hormone. The index patient had two other family members. To elucidate the pathogenesis of PA in this family and to help identify predisposed family members, we conducted a germline mutation analysis of the AIP and MEN1 genes in the index patient. No germline mutations in these genes were found but several SNPs. To our knowledge, this is the first AA family reported with non-MEN1/CNC familial isolated PA. In at least 10% of patients with clinical features of MEN1, no germline mutations in the MEN1 gene are identified. Therefore, there is still a remote chance that our family has an atypical MEN1 variant. In contrast to patients reported with germline mutations in the AIP gene, our patient and family members had hormonally inactive PA and SNPs in the AIP gene. SNPs in various genes, here in the AIP and MEN1 genes, may increase the predisposition of individuals to develop certain tumors and, in the family reported here, pituitary tumors.